To revise previous European Federation of Neurological Societies (EFNS) recommendations on the diagnosis and management of Alzheimer's disease (AD)

To present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with AD

Note: The following treatments were considered but not recommended due to insufficient or inconsistent evidence: any drugs, including anti-inflammatory drugs, nootropics (including piracetam, nicergoline), selegiline, oestrogens, pentoxifylline, statins, EGb 761 and Cerebrolysin in the treatment or prevention of Alzheimer's disease (AD); ChEIs, vitamin E, ginkgo and oestrogens to treat mild cognitive impairment; aspirin solely to treat AD

Major Outcomes Considered

Sensitivity, specificity, and accuracy of diagnostic tests

Efficacy of treatment (measured by rate of conversion to Alzheimer's disease, cognitive function, global outcome, activities of daily living, behavioral and psychiatric symptoms, timing of institutionalisation, and quality of life)

Methodology

Methods Used to Collect/Select the Evidence

Searches of Electronic Databases

Description of Methods Used to Collect/Select the Evidence

The evidence for this guideline was collected from Cochrane Library reviews, meta-analyses, and systematic reviews and original scientific papers published in peer-reviewed journals before May 2009 accessed using the MEDLINE database.

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence

Weighting According to a Rating Scheme (Scheme Given)

Rating Scheme for the Strength of the Evidence

Evidence Classification Scheme for a Diagnostic Measure

Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a 'gold standard' for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy

Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by 'gold standard') compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy

Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation

Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls)

Evidence Classification Scheme for a Therapeutic Intervention

Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:

Randomization concealment

Primary outcome(s) is/are clearly defined

Exclusion/inclusion criteria are clearly defined

Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias

Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences

Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment

In the revised guideline special attention was given to whether further evidence had become available for biomarkers of disease like magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) that have been proposed to increase the confidence of the clinical diagnosis. Special attention was given to results of recent clinical trials in Alzheimer's disease, both for cognitive and behavioral aspects of the disease.

The scientific evidence was evaluated according to pre-specified levels of certainty (classes of evidence I, II, III, and IV) by the expert group members.

Methods Used to Formulate the Recommendations

Expert Consensus

Description of Methods Used to Formulate the Recommendations

In 2008 a task force was set up to develop a revision of the European Federation of the Neurological Societies (EFNS) guideline for the diagnosis and management of Alzheimer's disease (AD) and other disorders associated with dementia, published in early 2007. A proposed guideline with specific recommendation was drafted for circulation to task force members and displayed on EFNS web pages for comments from all panel members. Consensus was reached at three task force meetings during 2009.

The recommendations were graded according to the strength of evidence (grade A, B, or C), using the definitions given in the EFNS guidance (see the "Rating Scheme for the Strength of the Evidence" field). In addressing important clinical questions, for which no evidence was available, 'good practice points' were recommended based on the experience and consensus of the expert task force group.

Rating Scheme for the Strength of the Recommendations

Rating of Recommendations for a Diagnostic Measure

Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent, convincing class II studies.

Recommendations

The levels of evidence (class I-IV) supporting the recommendations and ratings of recommendations (A-C, Good Practice Point) are defined at the end of the "Major Recommendations" field.

Recommendations for Diagnosis

Clinical history should be supplemented by an informant (Level A). A neurological and physical examination should be performed in all patients with dementia (Good Practice Point). Activities of daily living (ADL) impairment due to cognitive decline is an essential part of the diagnostic criteria for dementia and should be assessed in the diagnostic evaluation (Level A).

Several informant-based questionnaires are available and should be used where possible (Good Practice Point).

Cognitive assessment should be performed in all patients (Level A). Quantitative neuropsychological testing should be made in patients with questionable or very early Alzheimer's disease (AD) (Level B). The assessment of cognitive functions should include a general cognitive measure and more detailed testing of the main cognitive domains, and in particular an assessment of delayed recall (Level A). In patients with moderate memory impairment cued recall could be more appropriate than free recall (Level B).

Assessment of behavioral and psychological symptoms of dementia (BPSD) should be performed in each patient (Level A). Information should be gathered from an informant using an appropriate rating scale (Good Practice Point).

Assessment of co-morbidity is important in AD patients, both at the time of diagnosis and throughout the course of the illness (Good Practice Point) and should always be considered as a possible cause of BPSD (Level C). Blood levels of folate, vitamin B12, thyroid stimulating hormone, calcium, glucose, complete blood cell count, renal and liver function tests should be evaluated at the time of diagnosis and serological tests for syphilis, Borrelia, and human immunodeficiency virus (HIV) might also be needed in cases with atypical presentation or clinical features suggestive of these disorders (Good Practice Point).

Computed tomography (CT) and magnetic resonance imaging (MRI) may be used to exclude treatable causes of dementia. Multislice CT and coronal MRI may be used to assess hippocampal atrophy to support a clinical diagnosis of AD (Level B). Fluorodeoxy-glucose-positron emission tomography (FDG-PET) and perfusion single photon emission computed tomography (SPECT) are useful adjuncts when diagnosis remains in doubt (Level B). Dopaminergic SPECT is useful to differentiate AD from dementia with Lewy bodies (DLB) (Level A). Follow up with serial MRI is useful in a clinical setting to document disease progression (Good Practice Point).

Routine cerebrospinal fluid (CSF) analysis is recommended in differential diagnosis for atypical clinical presentations of AD (Good Practice Point). CSF 14-3-3 or total tau measurement are recommended for the identification of CJD in patients with rapidly progressive dementia (Level B). Alterations in CSF total tau, phospho-tau, and Aβ42 support diagnosis of AD (Level B).

Screening for known pathogenic mutations can be undertaken in patients with appropriate phenotype or a family history of an autosomal dominant dementia. Routine apolipoprotein E (Apo E) genotyping is not recommended.

Recommendations on Management

Diagnosis of AD should be disclosed to patient (and caregivers as appropriate) (Level B). Disclosure of diagnosis should be individually tailored. It should be accompanied by information and counseling, as well as useful contacts such as Alzheimer's patient organizations. Patients and caregivers should be provided with education and support (Level A). Driving, medico-legal issues, and the need for other support services should be considered (Good Practice Point). If possible physicians may encourage patients to draw up advance directives containing future treatment and care preferences (Good Practice Point).

There is insufficient evidence to support the use of any drugs purely for the primary prevention of dementia. Cholinesterase inhibitors (ChEIs), vitamin E, ginkgo, and oestrogens should not be used as treatments for those with mild cognitive impairment (MCI) (Level A).

In patients with AD, treatment with ChEIs (donepezil, galantamine, or rivastigmine) should be considered at the time of diagnosis, taking into account expected therapeutic benefits and potential safety issues (Level A). Benefits on cognitive and non-cognitive symptoms have been demonstrated in those with mild, moderate, and severe disease (Level A). Realistic expectations for treatment effects and potential side effects should be discussed with the patient and caregivers (Good Practice Point).

In patients with moderate to severe AD, treatment with memantine should be considered taking into account expected therapeutic benefits and potential safety issues (Level A). Benefits on cognitive and noncognitive symptoms are apparent, some non-cognitive symptoms (agitation, delusions) may respond better than others (Level B). Realistic expectations for treatment effects and potential side effects should be discussed with the patient and caregivers (Good Practice Point).

Regular patient follow-up, which should include scales like the Mini-Mental State Examination (MMSE) to monitor response to treatment and disease progression, should be an integral part of management (Good Practice Point).

Aspirin should not be used as a treatment for AD (Level A), though it can be used in those with AD who also have other indications for its use (e.g., to prevent cardiovascular events). Vitamin E should not be used as a treatment for AD (Level A).

Currently, there is insufficient evidence to support the use of other agents, including anti-inflammatory drugs, nootropics (including piracetam, nicergoline), selegiline, oestrogens, pentoxifylline, or statins and inconsistent evidence for EGb 761 and Cerebrolysin in the treatment or prevention of AD (Level A).

Cognitive stimulation or rehabilitation may be considered in patients with mild to moderate AD (Good Practice Point). Occupational therapy can improve patients' functioning and reduce need for informal care (Level B).

Management of BPSD should begin with a careful search for triggers and causative factors (i.e., physical illness). Where possible, initial treatment should be non-pharmacological (Level C).

Antipsychotics should only be used for moderate or severe BPSD symptoms causing significant distress which have either not responded to other treatments (like non-pharmacological measures or ChEIs) or when other treatments are not appropriate (Level A). Low dose of atypical agents should be used only after assessment of risk benefit and full discussion with patient (when capacity allows) and caregiver (Good Practice Point).

Atypical agents have fewer side effects and do not confer a greater risk of stroke or mortality than conventional drugs (Level B).

Selective serotonin reuptake inhibitors rather than tricyclic antidepressants should be used to treat depression in AD (Level B).

Definitions:

Evidence Classification Scheme for a Diagnostic Measure

Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a 'gold standard' for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy

Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by 'gold standard') compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy

Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation

Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls)

Evidence Classification Scheme for a Therapeutic Intervention

Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:

Randomization concealment

Primary outcome(s) is/are clearly defined

Exclusion/inclusion criteria are clearly defined

Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias

Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences

Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment

Evidence Supporting the Recommendations

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate diagnosis and management of Alzheimer's disease

Potential Harms

Cholinesterase inhibitors (ChEIs) are generally well tolerated, although common gastrointestinal adverse effects such as nausea, diarrhea, and vomiting may sometimes lead to discontinuation of treatment in some patients. One of the ChEIs, rivastigmine, is now available in a transdermal (patch) formulation which appears to have lower incidence of side effects than oral administration but equal efficacy.

Antipsychotics have important and potentially serious side effects, most especially increased stroke risk, increased mortality, parkinsonism, and cognitive impairment. They should be used with caution, at low dose, and for the shortest period needed only for those with moderate to severe symptoms causing distress and after careful assessment of risk and benefit and after discussion with caregiver and, where possible, patient. There is no evidence that conventional agents are any safer in regard to risk of stroke or mortality than atypical agents and they have a less established evidence base and greater side effects. Low doses of antipsychotics should be used with careful monitoring, and drugs prescribed for the minimum period required.

Qualifying Statements

Qualifying Statements

This guideline provides the view of an expert task force appointed by the Scientific Committee of the European Federation of Neurological Societies (EFNS). It represents a peer-reviewed statement of minimum desirable standards for the guidance of practice based on the best available evidence. It is not intended to have legally binding implications in individual cases.

This guideline represents desirable standards to guide practice, but may not be appropriate in all circumstances as clinical presentation of the individual patient and available resources should be taken into account.

Implementation of the Guideline

Description of Implementation Strategy

The European Federation of Neurological Societies has a mailing list and all guideline papers go to national societies, national ministries of health, World Health Organisation, European Union, and a number of other destinations. Corporate support is recruited to buy large numbers of reprints of the guideline papers and permission is given to sponsoring companies to distribute the guideline papers from their commercial channels, provided there is no advertising attached.

Implementation Tools

Staff Training/Competency Material

For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Authors have received speaker's and/or consultancy honoraria from Eisai, GE Healthcare, Janssen-Cilag, Lundbeck, Mertz, Shire, Novartis, Elan, Zentiva, Pfizer, Wyeth and Elan. For the conception and writing of this guideline no honoraria or any other compensation were received by any of the authors.

Continuing Medical Education questions are available to registered users from the EFNS Web site.

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on April 23, 2009. The information was verified by the guideline developer on June 12, 2009. This summary was updated by ECRI Institute on May 20, 2011 following the U.S. Food and Drug Administration advisory on antipsychotic drugs. This NGC summary was updated by ECRI Institute on November 20, 2012. The updated information was verified by the guideline developer on January 30, 2013.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the Wiley Online Library copyright restrictions.

Disclaimer

The National Guideline Clearinghouse™ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

All guidelines summarized by NGC and hosted on our site are produced under the auspices of medical specialty societies, relevant professional associations, public or private organizations, other government agencies, health care organizations or plans, and similar entities.

NGC, AHRQ, and its contractor ECRI Institute make no warranties concerning the content or clinical efficacy or effectiveness of the clinical practice guidelines and related materials represented on this site. Moreover, the views and opinions of developers or authors of guidelines represented on this site do not necessarily state or reflect those of NGC, AHRQ, or its contractor ECRI Institute, and inclusion or hosting of guidelines in NGC may not be used for advertising or commercial endorsement purposes.

Readers with questions regarding guideline content are directed to contact the guideline developer.